1. Field of the invention
This invention concerns .+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha. -hydroxybenzyl]pyrrolidines which affect the cardiovascular system and which are particularly effective as antihypertensive agents. The invention is directed mainly toward orally active, long lasting cardiovascular regulators of hypertension. However, the compounds of this invention are also potent bronchodilators.
The invention is also directed toward pharmaceutical compositions useful for management of hypertension and toward the method of use for regulating the cardiovascular system in mammals.
2. Related Disclosures
The invention herein concerns cyclic analogs of compounds known to possess molecular segments which affect peripheral nervous system receptors regulating the cardiovascular system. These compounds are also effective as bronchodilators.
Various physiological responses result from administering pharmaceuticals which affect the cardiovascular system regulating receptors. These responses may vary from vasodilation, vasoconstriction, tachycardia, bradycardia, positive or negative inotropic effect. Secondary effects such as bronchodilation or bronchoconstriction can also appear.
The physiological response depends on the exact nature of the drug. Therefore, various members of the same general class of compounds may be used in the treatment of cardiac disorders such as hypertension, cardiac arrhythmia, and vasal congestion.
The following resume represents a compilation of the known compounds which most closely resemble, in molecular structure, the compounds of the present invention, and which are useful in treating cardiovascular disorders and in other therapeutic applications.
Practolol and prenalterol which are amino-alcohol aryl ethers are well known and commercially available compounds which affect the .alpha..sub.1 adrenergic receptors of the peripheral system.
Sulfinolol, (British Pat. No. 1,544,872, published Apr. 25, 1979) and its relatives, are known antihypertensive/antiarrhythmic agents.
Deliberate attempts to combine .alpha..sub.1 affectors with vasodilators resulted in compounds such as naphthalenone phthalazinylhydrazones. Naphthalenone phthalazinylhydrazones may be hydrolyzed in the body to form a well known peripheral vasodilator hydralazine, and a general .alpha. adrenergic blocker bunolol, (see U.S. Pat. No. 4,061,636).
Cyclic compounds containing a 5 or 6 membered saturated nitrogen-containing ring, linked through a hydroxymethyl group to an aromatic nucleus, such as, for example, rimeterol (Pinder, R. M. et al, Drugs, 14:81 (1977)) and other compounds disclosed in European Pat. No. 10460, published Apr. 30, 1980 are known psychotropic and hypolipaemic agents. Rimeterol, itself, is a known .alpha..sub.2 agonist which is effective when given parentherally, but not effective when administered orally. Some of these compounds have recently been described as having hypotensive effect (See European Pat. No. 22408).
British Pat. No. 1,392,674, published Apr. 30, 1975, discloses compounds related in structure to those of the current invention which are useful for treatment of acute slowdown cardiac contractility.
U.S. Pat. No. 4,342,692 and its EPO counterpart disclose a family of compounds which may be interpreted to be similar to the compounds of the current invention. U.S. Pat. No. 3,655,693 discloses salicylic acid derivatives useful in the treatment of inflammation. U.S. Pat. No. 3,984,200 discloses mono or dihydroxyphenylalkyl dopamine derivatives useful as inotropic agents.
The present invention is directed toward orally active, long acting cardiovascular regulators. The compounds combine, in a sterically controlled way, two segments related to structures showing analogous activities (i.e. an arylhydroxymethyl or benzyl moiety bridged through a short chain to nitrogen and another aromatic group also linked to a nitrogen), by joining these through a common nitrogen atom cyclized to form a pyrrolidine ring.
The compound of this invention have a strong antihypertensive activity. The antihypertensive activity of the compounds of this invention is best shown by their effect on the systolic blood pressure. The compounds of this invention decrease significantly the systolic blood pressure without at the same time increasing heart rates. Moreover, the dosage which is needed to decrease systolic blood pressure is very low and the secondary, often undesirable, side effects are thus avoided. Thus, this invention offers the effective management of hypertension without submitting the treated subject to the undesirable secondary effects which would be unavoidable if large doses are needed.